Association of Transforming Growth Factor β Polymorphism C-509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed.

Objective: To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy.

Design, setting, and participants: This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression.

Exposures: A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene.

Main outcomes and measures: The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy.

Results: Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P = .02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P = .02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P < .001) were significantly associated with breast fibrosis risk.

Conclusions and relevance: To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer.

Trial registration: ClinicalTrials.gov identifier: NCT01266642.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Woodward reported serving as a paid consultant for Merck Sharp & Dohme Corp. Dr Smith reported receiving financial support from Varian Medical Systems, the Cancer Prevention & Research Institute of Texas, and the National Cancer Institute of the National Institutes of Health and through a fellowship from the Andrew Sabin Family Foundation. No other disclosures were reported.

Figures

Figure 1.. Study Enrollment Flowchart

CF indicates conventionally fractionated; HF, hypofractionated; and WBI, whole-breast irradiation.

Figure 2.. Frequency of Breast Cancer Treatment Outcomes Scale (BCTOS) Subscale Scores Among Patients With Genotypes C/C vs C/T or T/T at Position −509 of the TGFB1 Gene

Each subscale score is the mean of the ratings of all items belonging to that subscale. Each item evaluates the difference between the treated and untreated breast on a 4-point ordinal scale: 1, indicates no difference; 2, slight difference; 3, moderate difference; 4, large difference. Scores are assorted into 0.2-U bins.